While inflammation is a common component of many clinical disorders, the contributing factors can be distinct. In recent years, the complement system has been associated with a growing number of inflammatory conditions that include acute and chronic tissue inflammation, adverse reactions to biomaterials, and transplant rejection. It is evident that excessive or insufficiently controlled complement activation on host cells can cause an immune imbalance that, exacerbated by factors such as oxidative stress or infection, may fuel a vicious cycle between complement, inflammation, and tissue damage. As a consequence, therapeutic modulation of complement emerges as attractive target for upstream inhibition of inflammatory processes but requires profound understanding of underlying processes, identification of rewarding targets, and careful selection of suitable inhibitors. This Program Project therefore employs a highly integrated and holistic approach to describe common and distinct denominators of complement involvement in inflammatory conditions and open avenues for improved therapeutic strategies. For this purpose, three disease models that are representative of the wide spectrum of complement-mediated conditions and have high impact for health care and the clinic will be thoroughly investigated. Whereas inflammatory reactions to hemodialysis and kidney transplantation (Project 2) represent distinct disorders of complement activation by artificial and foreign surfaces and major complications in end-stage renal disease, periodontitis (Project 3) is an emerging and very attractive model of local tissue inflammation with a strong infectious component. Using relevant in vitro assays, sensitive instrumental methods (Core 6), and translational models in rodents and non-human primates, disease processes will be investigated in relation to complement triggers and activity, but also to associated pathways (e.g., TLR), effects on downstream inflammatory processes, and influences of modulating factors (e.g., oxidative damage, infection). A diverse panel of potent, validated, pathway-specific and/or targeted complement inhibitors will be generated (Project 1, Core B) that allows for the dissection of involved complement pathways and processes in each disease. This 'inhibitor toolbox' includes analogs of the central C3 inhibitor compstatin, which will serve as a benchmark compound, and entities acting at individual initiation, amplification, and effector pathways. Optimization of efficacy, pharmacokinetic, administration, and targeting properties will be guided by results and requirements of the disease models of Projects 2 & 3. At the same time, the evaluation of promising and pre-validated inhibitor candidates in such relevant disease models is expected to allow rapid translation into therapeutic concepts. Established models, methods, and inhibitors of this P01 can easily be applied to future disease studies. Thus, this P01 will have a high impact on the elucidation and management of complement-related disease and benefit patients and the research community.